Project Summary This R21 application is responsive to NIA PA-18-153 Prevention Research in Mid-Life Adults. Systolic hypertension, defined as systolic blood pressure (SBP) ?130 mmHg, affects 65-70% of mid-life adults (50-64 years), and is a major modifiable risk factor for cardiovascular diseases, cognitive decline/dementia, renal dysfunction and other chronic conditions of aging. Many mid-life adults do not engage in time-intensive healthy lifestyle practices that would reduce SBP due to competing personal and professional time demands that tend to peak during this period of life. The number of mid-life adults is rapidly increasing, necessitating the development of novel, time- and effort-efficient lifestyle interventions to prevent and treat systolic hypertension. Co-I Dr. Fiona Bailey has found that brief (~5 min/day) inspiratory muscle strength training (IMST) consisting of 30 breaths at 75% of maximal inspiratory pressure (PIMAX), 5-6 days/week for 6 weeks lowers casual (resting) SBP by 12 mmHg in patients with obstructive sleep apnea (OSA), with excellent adherence (<10% dropout, 97% of training sessions completed). A primary cause of systolic hypertension with aging is arterial stiffening, demonstrated by increased carotid-femoral pulse wave velocity (CFPWV). Findings in OSA patients and healthy young adults show that IMST reduces systemic vascular resistance and plasma norepinephrine (PNE), a marker of sympathetic activity and vascular smooth muscle constrictor, suggesting actions on vascular tone/stiffness. Oxidative stress-mediated inhibition of nitric oxide (NO) bioavailability and its tonic vasodilatory influence is another key determinant of arterial stiffening that may play a role in IMST- induced improvements in SBP. However, the short-term and long-lasting effects of IMST on SBP, arterial function, sympathetic activity and oxidative stress, and its safety and adherence, in mid-life adults is unknown. We propose a small randomized, double-blind, sham-controlled, parallel design clinical trial to assess the efficacy of 6-weeks of IMST (75% PIMAX) vs. sham training (15% PIMAX) (n=23/group) for decreasing SBP and improving arterial function in mid-life adults with systolic hypertension. We hypothesize that IMST will lower SBP and CFPWV, and increase brachial artery flow-mediated dilation (FMDBA), a measure of NO-mediated endothelium-dependent dilation, and reduce oxidative stress and PNE. We further hypothesize that IMST will be safe, well-tolerated, and associated with high rates of adherence, and that a portion of the improvements in SBP and arterial function will persist 6-weeks after completing post-intervention testing. Aim 1: To measure casual SBP (primary outcome) and 24-hour ambulatory SBP (secondary outcome) before, after and 6-weeks following IMST vs. sham training. Safety, tolerability and adherence will also be assessed; Aim 2: To measure CFPWV, FMDBA and PNE before, after and 6-weeks following IMST vs. sham training; Aim 3: To evaluate tonic oxidative stress-mediated suppression of FMDBA, and markers of oxidative stress and antioxidant defense in endothelial cells from subjects before, after and 6-weeks following IMST/sham training.